阿爾茨海默病的靜息態(tài)功能磁共振、彌散張量成像及腦灌注研究進(jìn)展

【摘要】阿爾茨海默病(Alzheimer’s disease，AD)以認(rèn)知和記憶能力下降為主要特征，輕度認(rèn)知功能障礙是AD的早期階段，AD的病理生理機(jī)制目前尚不清楚，本文綜述了AD有關(guān)的神經(jīng)影像學(xué)研究，通過應(yīng)用磁共振成像新技術(shù)包括靜息態(tài)腦功能成像、彌散張量成像、腦灌注成像，有助于我們從功能、結(jié)構(gòu)和灌注的角度更深入理解AD的病理生理機(jī)制。本文對此做簡要綜述。

［doi: 10．3969/j．issn．1006-7795．2015．04．025］·轉(zhuǎn)化醫(yī)學(xué)研究·

基金項目:國家自然科學(xué)基金(81471649，81370037)，北京市自然科學(xué)基金(7153166)。This study was supported by National Natural Science Foundation of China(81471649，81370037)，Natural Science Foundation of Beijing(7153166)．* Corresponding author，E-mail: likuncheng1955@ aliyun．com

網(wǎng)絡(luò)出版時間: 2015－07－16 23∶13網(wǎng)絡(luò)出版地址: http:∥www．cnki．net/kcms/detail/11．3662．r．20150716．2313．028．html

Resting state functional MRI，DTI and PWI in the Alzheimer’s disease

Wang Zhiqun 1，Li Kuncheng 2，3，4*

(1．Department of Radiology，Dongfang Hospital of Beijing University of Chinese Medicine，Beijing 100078，China; 2．Department of Radiology，Xuanwu Hospital，Capital Medical University，Beijing 100053，China; 3．Key Laboratory for Neurodegenerative Disorders of the Ministry of Education，Capital Medical University，Beijing 100053，China; 4．Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics，Beijing 100053，China)

【Abstract】Alzheimer’s disease(AD)is characterized as cognitive and memory decline．Mild cognitive impairment(MCI)is the early stage of AD．The pathophysiology of AD is not very clear．In the present article，we reviewed the previous neuroimaging study of AD．By using the new MRI techniques including resting state functional MRI(fMRI)，diffusion tensor imaging(DTI)and perfusion weighted imaging(PWI)，we can acquire deep understanding of the pathophysiology of AD from the prospect of function，structure and perfusion．

【Key words】Alzheimer’s disease; mild cognitive impairment; functional MRI; diffusion tensor imaging; perfusion weighted imaging

Alzheimer’s disease(AD)is a progressive neurodegenerative disorder manifested by cognitive and memory decline．It is characterized pathologically by amyloid-β plaques，neurofibrillary tangles and neuronal loss ［1］．Mild cognitive impairment(MCI)is a transitional period between normal aging and AD．About 10%-15% of MCI patient progress to develop dementia annually ［2］．The pathophysiology of AD，however，remains not very clear．In the recent years，several neuroimaging methods were applied to the AD and MCI to try to explore the pathogenesis of AD and MCI．Resting state functional MRI(fMRI)provides the brain functional activity and connectivity changes in AD patients．Diffusion tensor imaging(DTI)demonstrates the white matter structure injury in AD patients．In addition，perfusion weighted imaging(PWI)focuses on the cerebral blood dysfunction in AD patients．In order to acquire deep understanding of the pathophysiology of AD，in the following paragraph，we will introduce the application of these methods in AD patients in details．

1　　Resting state functional MRI in Alzheimer’s disease

Recently，increasing attention has focused on exploring brain activity during resting-state fMRI．Restingstate fMRI may have potential for clinical studies and ap-plications due to its superior non-radioactivity and its easy application relative to task-driven fMRI．Biswal et al． ［3］for the first time showed that functionally related brain regions exhibit correlation of low-frequency(＜0．08 Hz)blood oxygen level dependent(BOLD)fluctuations as detected by resting-state fMRI．The researchers reached consensus that the low-frequency BOLD signals by resting fMRI may reflect spontaneous neuronal activity in the brain．Since then，resting-state fMRI has attracted more attention and has been applied to the studies of various neuropsychiatric diseases especially AD and MCI．To date，several groups have utilized this technique to examine the changes in intrinsic brain activity in AD and MCI ［4-12］．These intriguing studies of resting-state fMRI have provided a good insight into the pathophysiology of AD and MCI．Using a variety of region of interest(ROI)based or whole brain analyses，consistent reductions in functional connectivity or large-scale brain networks have been reported by independent groups in AD patients，which indicated the disconnection syndrome of AD．The resting-state fMRI studies of AD can be generally divided into two distinct categories according to the research methods used．

1．1 Regional brain activity analysis

By measuring the cross-correlation coefficients of spontaneous low frequency fluctuations(COSLOF)，Li et al． ［4］found that AD and MCI patients exhibited decreased spontaneous brain activity in the hippocampus that could be used to further differentiate the patients from healthy elders．Maxim et al． ［6］found that AD patients had greater persistence of resting fMRI noise in several brain regions such as the medial and lateral temporal lobes，dorsal cingulate/medial premotor cortex，and insula．Using a recently developed regional homogeneity method，He et al． ［9］showed that AD patients had abnormal spontaneous activity in the posterior cingulate region．Bai et al． ［11］found default-mode network was impaired in MCI subjects by using the regional homogeneity method．Recently，Zang and colleagues ［13］proposed a measure，amplitude of low frequency fluctuations(ALFF)obtained by calculating the square root of the power spectrum in the frequency range of 0．01-0．08 Hz to assess the magnitude of resting-state spontaneous brain activity．Using ALFF，Wang and colleagues explored the abnormal spatial patterns of intrinsic brain activity in MCI and AD．We found the ALFF of posterior cingulate cortex(PCC)can differentia AD and normal controls with a high sensitivity and specificity ［14］．

1．2 Functional connectivity analysis

Recent resting fMRI studies have demonstrated the changes in functional connectivity in the brain of AD patients by using region of interest ［7-8，12］．The hippocampus is believed to constitute memory network to modulate and facilitate communication．By using bilateral hippocampi as“seed”regions，the researchers demonstrated markedly reduced functional connectivity in hippocampus-related networks in the AD patients ［7］and MCI patients ［15-16］．With a temporal correlation method，Zhang et al． ［12］examined the characteristics of resting-state functional connectivity of PCC with the other brain regions in the AD patients and demonstrated decreased connectivity to the several brain regions，including the ventral medial prefrontal cortex(MPFC)and the precuneus，the dorsal lateral prefrontal cortex(DLPFC)，the hippocampus，inferior parietal lobe．By examining PCC connectivity，Wang and colleagues ［17］explored the baseline and longitudinal changes of PCC connectivity in MCI patients．Recently，by using subregions of inferior parietal lobular(IPL)as seed regions，our groups found the IPL connectivity are differently affected in AD ［18］and MCI patients ［19］．By using anterior and posterior insula as seed regions，Xie et al． ［20］explored the insular connectivity and its association with memory in MCI patients．By application of resting state fMRI，Wang et al． ［21］found decreased connectivity of thalamus to bilateral cuneus，superior frontal gyrus(SFG)，MPFC，precuneus，inferior frontal gyrus(IFG)and precentral gyrus(PreCG)in MCI patients．By examining the correlations among ninety regions of the whole brain，Wang et al． ［8］showed decreased functional connectivity between anterior-posterior regions but increased connectivity between within-lobe regions．

Within the resting-state networks，the default mode network(DMN)is of high interest for the AD field be-cause it correlates with episodic memory functioning and attentional processing．The DMN typically consists of the PCC，the precuneus，retrosplenial cortex，IPL，MPFC，the medial temporal regions as well as lateral temporal lobe．Using independent component analyses(ICA)，greicius and colleagues ［5］found decreased spontaneous brain activity within DMN ［22-23］in the AD patients．Sorg et al． ［10］showed eight spatially consistent resting-state brain networks by ICA，and found only selected areas of the DMN and the executive attention network demonstrated markedly reduced activity in the MCI patients．Qi et al． ［24］found impairment and compensation of DMN coexist in MCI patients．Recently，by using ICA method，researchers found more different disrupted resting state networks in AD patients，which beyond the DMN ［25］．

2　DTI study in Alzheimer’s disease

Diffusion tensor imaging(DTI)is a noninvasive technique that can be used to reflect the microstructural tissue status and orientations．It has been applied in AD and MCI to detect the white matter injury in the key regions and the whole brain．By examining the gateway to the limbic system with DTI，researchers found the disruption of the perforant pathway in AD ［26］．By exploring the changes in parahippocampal white matter integrity，researchers found white matter pathology isolates the hippocampal formation in AD ［27］．Recently，several studies investigated the white matter changes in AD by using diffusion tensor tractography(DTT)．For example，the researcher used fiber bundles to visualize the connectivity in posterior cingulate cortex and hippocampus and found the gradually decreased connectivity as the pattern of normal＞MCI＞AD ［28］．With the advanced tractography technique and parameter measurement，researchers found diffusion abnormality in the posterior cingulum in AD and concluded that MD in the posterior cingulum appears to be a sensitive indicator of disease progression of AD ［29］．Most recently，Voxel-based tract based spatialstatistics(TBSS)，a new analysis method was developed to explore whole-brain maps of main white matter bundles for fractional anisotropy(FA)，radial diffusivity(DR)，axial diffusivity(DA)and mean diffusivity(MD)．By multiple DTI index analysis in AD and MCI，our group found disconnection in several brain regions，with particular emphasis on the hippocampal white matter and the posterior cingulum．In addition，there is some evidence that changes in DR，a potential marker of myelin damage，is more common in AD and MCI than changes in DA，an indicator of axonal damage ［30］．

3　PWI study in Alzheimer’s disease

Arterial spin-labeling magnetic resonance imaging(ASL-MRI)，which labels arterial blood water as an endogenous diffusible tracer for perfusion，may be able to detect functional deficiencies in a way similar to positron emission tomography(PET)．Recent study demonstrated the pattern of cerebral hypoperfusion in AD measured with ASL-MRI and found the most significant hypoperfusion is in the posterior cingulate gyri and parietal association cortices ［31］．Most recently，researchers measured the cerebral blood flow(CBF)with 3D whole brain ASL MR Imaging in AD and MCI．They concluded that CBF can detect functional changes in the prodromal and more advanced stages of AD and is a marker for disease severity ［32］．

4　Summary

In the future，there are several issues need to addressed．Firstly，combination of multi-modal neuroimaging approaches(resting fMRI，structural and diffusion MRI，perfusion MRI)will yield a more comprehensive understanding of AD．Secondly，by application of these new imaging techniques，we can try to clarify the different type of dementia such as AD，frontal temporal dementia(FTD)，vascular dementia(VD)，lewy body dementia(DLB)．Finally，we will aim to find most sensitive and specific neuroimaging biomarker to diagnose AD as early as possible，such as preclinical AD．

5 References

［1］　Braak H，Braak E．Neuropathological stageing of Alzheimerrelated changes［J］．Acta Neuropathol，1991，82(4): 239-259．

［2］　Petersen R C，Doody R，Kurz A，et al．Current concepts in mild cognitive impairment［J］．Arch Neurol，2001，58(12): 1985-1992．

［3］　Biswal B，Yetkin F Z，Haughton V M，et al．Functional connectivity in the motor cortex of resting human brain using echo-planar MRI［J］．Magn Reson Med，1995，34(4): 537-541．

［4］　Li S J，Li Z，Wu G，et al．Alzheimer Disease: evaluation of a functional MR imaging index as a marker［J］．Radiology，2002，225(1): 253-259．

［5］　Greicius M D，Srivastava G，Reiss A L，et al．Defaultmode network activity distinguishes Alzheimer＇s disease from healthy aging: evidence from functional MRI［J］．Proc Natl Acad Sci U S A，2004，101(13): 4637-4642．

［6］　Maxim V，Sendur L，F(xiàn)adili J，et al．Fractional Gaussian noise，functional MRI and Alzheimer＇s disease［J］．Neuroimage，2005，25(1): 141-158．

［7］　Wang L，Zang Y，He Y，et al．Changes in hippocampal connectivity in the early stages of Alzheimer＇s disease: evidence from resting state fMRI［J］．Neuroimage，2006，31(2): 496-504．

［8］　Wang K，Liang M，Wang L，et al．Altered functional connectivity in early Alzheimer＇s disease: a resting-state fMRI study［J］．Hum Brain Mapp，2007，28(10): 967-978．

［9］　He Y，Wang L，Zang Y，et al．Regional coherence changes in the early stages of Alzheimer＇s disease: a combined structural and resting-state functional MRI study［J］．Neuroimage，2007，35(2): 488-500．

［10］Sorg C，Riedl V，Muhlau M，et al．Selective changes of resting-state networks in individuals at risk for Alzheimer＇s disease［J］．Proc Natl Acad Sci U S A，2007，104(47): 18760-18765．

［11］Bai F，Zhang Z，Yu H，et al．Default-mode network activity distinguishes amnestic type mild cognitive impairment from healthy aging: a combined structural and resting-state functional MRI study［J］．Neurosci Lett，2008，438(1): 111-115．

［12］Zhang H Y，Wang S J，Liu B，et al．Resting brain connectivity: changes during the progress of Alzheimer disease［J］．Radiology，2010，256(2): 598-606．

［13］Zang Y F，He Y，Zhu C Z，et al．Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI［J］．Brain Dev，2007，29(2): 83-91．

［14］Wang Z，Yan C，Zhao C，et al．Spatial patterns of intrinsic brain activity in mild cognitive impairment and alzheimer＇s disease: A resting-state functional MRI study［J］．Hum Brain Mapp，2011，32(10): 1720-1740．

［15］Bai F，Xie C，Watson D R，et al．Aberrant hippocampal subregion networks associated with the classifications of aMCI subjects: a longitudinal resting-state study［J］．PLoS One，2011，6(12): e29288．

［16］Wang Z，Liang P，Jia X，et al．Baseline and longitudinal patterns of hippocampal connectivity in mild cognitive impairment: evidence from resting state fMRI［J］．J Neurol Sci，2011，309(1-2): 79-85．

［17］Wang Z，Liang P，Jia X，et al．The baseline and longitudinal changes of PCC connectivity in mild cognitive impairment: a combined structure and resting-state fMRI study ［J］．PLoS One，2012，7(5): e36838．

［18］Wang Z，Xia M，Dai Z，et al．Differentially disrupted functional connectivity of the subregions of the inferior parietal lobule in Alzheimer＇s disease［J］．Brain Struct Funct，2015，220(2): 745-762．

［19］Liang P，Wang Z，Yang Y，et al．Three subsystems of the inferior parietal cortex are differently affected in mild cognitive impairment［J］．J Alzheimers Dis，2012，30(3): 475-487．

［20］Xie C，Bai F，Yu H，et al．Abnormal insula functional network is associated with episodic memory decline in amnestic mild cognitive impairment［J］．Neuroimage，2012，63(1): 320-327．

［21］Wang Z，Jia X，Liang P，et al．Changes in thalamus connectivity in mild cognitive impairment: evidence from resting state fMRI［J］．Eur J Radiol，2012，81(2): 277-285．

［22］Greicius M D，Krasnow B，Reiss A L，et al．Functional connectivity in the resting brain: a network analysis of the default mode hypothesis［J］．Proc Natl Acad Sci U S A，2003，100(1): 253-258．

［23］Raichle M E，MacLeod A M，Snyder A Z，et al．A default mode of brain function［J］．Proc Natl Acad Sci U S A，2001，98(2): 676-682．

［24］Qi Z，Wu X，Wang Z，et al．Impairment and compensation coexist in amnestic MCI default mode network［J］．Neuroimage，2010，50(1): 48-55．

［25］Agosta F，Pievani M，Geroldi C，et al．Resting state fMRI in Alzheimer＇s disease: beyond the default mode network ［J］．Neurobiol Aging，2012，33(8): 1564-1578．

［26］Kalus P，Slotboom J，Gallinat J，et al．Examining the gateway to the limbic system with diffusion tensor imaging: the perforant pathway in dementia［J］．Neuroimage，2006，30(3): 713-720．

［27］Rogalski E J，Murphy C M，deToledo-Morrell L，et al．Changes in parahippocampal white matter integrity in amnestic mild cognitive impairment: a diffusion tensor imagingstudy［J］．Behav Neurol，2009，21(1): 51-61．

［28］Zhou Y，Dougherty J H Jr，Hubner K F，et al．Abnormal connectivity in the posterior cingulate and hippocampus in early Alzheimer＇s disease and mild cognitive impairment ［J］．Alzheimers Dement，2008，4(4): 265-270．

［29］Nakata Y，Sato N，Nemoto K，et al．Diffusion abnormality in the posterior cingulum and hippocampal volume: correlation with disease progression in Alzheimer＇s disease［J］．Magn Reson Imaging，2009，27(3): 347-354．

［30］Shu N，Wang Z，Qi Z，et al．Multiple diffusion indices reveals white matter degeneration in Alzheimer＇s disease and mild cognitive impairment: a tract-based spatial statistics study［J］．J Alzheimers Dis，2011，26(Suppl 3): 275-285．

［31］Johnson N A，Jahng G H，Weiner M W，et al．Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin－labeling MR imaging: initial experience［J］．Radiology，2005，234(3): 851-859．

［32］Binnewijzend M A，Kuijer J P，Benedictus M R，et al．Cerebral blood flow measured with 3D pseudocontinuous arterial spin-labeling MR imaging in Alzheimer disease and mild cognitive impairment: a marker for disease severity ［J］．Radiology，2013，267(1): 221-230．

(收稿日期: 2014-01-13)

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